PROJECT SUMMARY/ABSTRACT Our parent R01 is examining the role of exposure to metals and risk of Alzheimer's disease (AD). In a case-control study nested within a VA medical center, we are assessing exposure to metals in early life and late life using metals in teeth and bone as biomarkers of exposure. In addition we are also examining the association between metal exposures and toxic A? species in plasma and brain tissue form the cases. Teeth are collected when extracted for other reasons (controls are recruited from an onsite dental clinic) or postmortem in the cases. Metals in circulation during the time of teeth formation are deposited in the teeth. We will measure metal levels in the enamel of the teeth to estimate early life exposures. Enamel formation occurs in the early childhood years and once formed does not turn over, thus reflecting early life exposures even in adult teeth in old age. Other parts of the tooth are formed over adult life and so metals in those parts of the tooth provide an estimate of adult exposures. Bone lead is measured non-invasively with X-Ray Fluorescence (XRF) techniques that have been used extensively in other research. The current ViCTER proposal will extend the parent R01 aims by allowing us to explore genetic variations in our case-control population that could contribute to differential susceptibility to metals in the context of AD risk. Metal neurotoxicity is determined by intricate interplays between metals and target neural cells, and there is overwhelming evidence documenting the detrimental effects of metals in neurons. Despite well- documented adverse effects of metals in neurons, how metals cause detrimental changes remains to be defined. Likewise, it is unclear which of the candidate mechanisms may be most relevant for AD susceptibility. Our fundamental hypothesis behind this new proposal is that there exist specific, yet-to-be- discovered human genes and genetic pathways that render some people more susceptible to developing AD when exposed to metals. Our high-risk, high-reward proposal will take advantage of our recent work creating neuronal cell lines from blood-derived induced pluripotent stem cells (iPSCs). We will create cell lines from our AD cases and controls enrolled in our parent grant and use these in experimental studies to identify transcriptomic and protein changes induced by metal exposures and changes that differ by AD status. We will then sequence the genome of the same AD cases and controls from which the neuronal cell lines were derived to identify variants in the genes showing the transcriptomic and protein changes in response to metal exposure. We will then access an existing much larger set of AD cases and controls to examine the extent to which genetic variants identified in our R01 AD cases and controls are found in a larger sample.